Neuromuscular blockade in mechanically ventilated pneumonia patients with moderate to severe hypoxemia: A multicenter retrospective study

Background/Purpose The benefit of neuromuscular blockades (NMBs) in critically ill patients receiving mechanical ventilation remains uncertain. Therefore, we aimed to investigate whether NMB use is associated with improved survival of mechanically ventilated pneumonia patients with moderate to severe hypoxemia. Methods This retrospective multicenter study was conducted at five university-affiliated hospitals. Data of pneumonia patients aged 18 years and older who received mechanical ventilation between January 1, 2011, and December 31, 2020, were analyzed. Results In a total of 1,130 patients, the mean patient age was 73.1 years (SD±12.6), and the overall mortality rate at 30 d was 29.5% (n = 333). NMB users had a higher 30 d mortality rate than NMB nonusers (33.9% vs. 26.8%, P = 0.014). After PS matching, the 30 d mortality rate was not significantly different between NMB users and nonusers (33.4% vs. 27.8%, p = 0.089). However, 90 d mortality rate was significantly increased in NMB users (39.7% vs. 31.9%, p = 0.021). Univariable Cox proportional hazard regression analyses showed that NMB use ≥ 3 d was significant risk factor for the 90 d mortality than those with < 3 d use (90 d mortality HR 1.39 [95% CI: 1.01–1.91], P = 0.045). Conclusions NMB use was not associated with lower 30 d mortality among mechanically ventilated pneumonia patients with moderate to severe hypoxemia. Rather, NMB users had higher 90 d mortality, furthermore, and NMB use ≥ 3 d was associated with a higher risk of long-term mortality compared to NMB use < 3 d. Therefore, care should be taken to avoid extended use of NMB in critically ill pneumonia patients during mechanical ventilation.


Introduction
During mechanical ventilation, neuromuscular blockades (NMBs) have been used in various critical care settings such as acute respiratory distress syndrome (ARDS) [1][2][3][4][5], severe sepsis [6,7], bronchospasm with profound hypoxemia [8], and therapeutic hypothermia [9,10]. The expected advantages of NMBs are a reduction of oxygen consumption, improvement of oxygenation, and optimization of mechanical ventilation through reducing patient-ventilator asynchrony [11]. However, it has been reported that the use of NMBs does not affect oxygen consumption in adequately sedated patients [12,13]. In addition, the use of NMBs may be associated with increased atelectasis, prolonged paralysis following NMB, and intensive care unit (ICU)-acquired weakness [11,14]. Therefore, NMBs should be used with caution in critically ill patients receiving mechanical ventilation.
It is well established that by reducing the risk of ventilator-induced lung injury, lung-protective mechanical ventilation can improve survival among patients with ARDS [15]. To facilitate lung-protective mechanical ventilation, a short course of NMB has been recommended in the early phase of moderate-to-severe ARDS [5,16,17]. In the ARDS et Curarisation Systematique (ACURASYS) trial, the early administration of a 48 h infusion of NMB in ARDS improved the adjusted 90 d survival for patients with a PaO 2 /FiO 2 ratio < 150. Furthermore, a systematic review and meta-analysis using three randomized trials revealed that a short-term course of NMB was associated with reduced mortality and did not increase ICU-acquired weakness for patients with ARDS [4]. However, a recently reported trial, the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial, showed that there was no significant difference in 90 d mortality between patients who received an early cisatracurium infusion and those who were treated with a lighter sedation strategy [18]. With this finding contradicting the supposed efficacy of NMBs in ARDS, the benefit of NMBs remains uncertain in critically ill patients receiving mechanical ventilation. Therefore, we aimed to investigate whether NMB use is associated with improved survival among mechanically ventilated pneumonia patients with moderate to severe hypoxemia.

Study design and patients
This retrospective multicenter study was conducted at five university-affiliated hospitals of Hallym University Medical Center in the Republic of Korea. The overall bed capacity and annual inpatients were approximately 3,000 beds (231 ICU beds) and 100,000 patients. We collected the electronic medical records of patients aged 18 years and older who received mechanical ventilation in the ICU between January 1, 2011, and December 31, 2020. During the study period, severe COVID-19 patients did not hospitalize at our ICUs. Among the mechanically ventilated patients identified, we enrolled patients with pneumonia. According to the clinical practice guideline of ARDS [19], NMBs have been used in moderate to severe hypoxemia to facilitate mechanical ventilation. Patients were excluded if they received surgery, underwent extracorporeal membrane oxygenation (ECMO) therapy, or had a duration of mechanical ventilation < 3 d. We further excluded patients with PaO 2 (partial pressure of oxygen)/FiO 2 (fraction of inspired oxygen) � 150 mmHg based on the initial arterial blood gas analysis. Patients received a bolus injection of NMB were excluded.
This study was approved by the Institutional Review Board of Chuncheon Sacred Heart Hospital (2021-03-011). The requirement for informed consent was waived owing to the retrospective nature of the analysis.

Data collection and definitions
We obtained the following data on the day of initiation of mechanical ventilation through clinical big data analytic solution Smart CDW, which can analyze the electronic medical record text and integrated fixed data at five hospitals: patient age, sex, body mass index, diagnosis, time from hospitalization to ICU admission, time from hospitalization to mechanical ventilation initiation, Acute Physiology and Chronic Health Evaluation (APACHE) II score, modified early warning score, CURB-65, transfer from a skilled nursing facility, Charlson Comorbidity Index (CCI) and its variables, continuous renal replacement therapy, transfusion, vasopressors or inotropes, corticosteroids, opioids (morphine, fentanyl, or remifentanil), sedatives (propofol, midazolam, or dexmedetomidine), type and infused duration of NMBs (cisatracurium and vecuronium), and laboratory results with arterial blood gases.
In the assigned diagnoses for each patient, we retrieved pneumonia using the KCD-7 codes (Korean version of the International Classification of Diseases-10, ICD-10). Comorbidities were categorized by CCI variables according to the ICD-10 codes. The CURB-65 score is comprised of five separate elements, including confusion, urea (> 19 mg/dL), respiratory rate (� 30/min), blood pressure (systolic blood pressure < 90 mmHg or diastolic blood pressure � 60 mmHg diastolic), and age (� 65 years) [20]. ARDS was identified as ICD-10 code of J80. To avoid inclusion of NMB users with bolus injection for endotracheal intubation purpose, we defined NMB users as patients who received continuous infusion of NMBs. The primary outcome was 30 d mortality from the initiation of mechanical ventilation. The secondary outcomes were 90 d mortality, length of stay, ICU stay, duration of mechanical ventilation, and the use of quetiapine and amiodarone.

Statistical analysis
To construct a control group (NMB nonusers), propensity score (PS) matching was performed by the nearest-neighbor method with the following variables: age, sex, body mass index, time from hospitalization to ICU admission, time from hospitalization to mechanical ventilation initiation, APACHE II score, modified early warning score, CURB-65, transferred from skilled nursing facility, CCI, aspiration pneumonia, diabetes, congestive heart failure, myocardial infarction, chronic pulmonary disease, liver disease, moderate to severe chronic kidney disease, any malignancy, rheumatic disease, dementia, cerebrovascular disease, continuous renal replacement therapy, transfusion, vasopressors and inotropes, corticosteroids, opioids, sedatives, and PaO 2 /FiO 2 . In the matching process, 37 patients in the study groups were excluded due to null values of the matching variables.
Differences in continuous and categorical baseline characteristics between the groups were analyzed with Student's t-test and the chi-square test, respectively. Moreover, differences in baseline characteristics in the 1:1 matched group were analyzed with the paired t-test and McNemar's test. Univariable and multivariable stratified Cox proportional hazard regression models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of mortality. Multivariate regression analysis was used to adjust the effect of imbalance in the baseline. Age, modified early warning score, Charlson comorbidity index, and positive end expiratory pressure (PEEP) were selected as the adjust variables, because there were significant differences between two groups even after matching. Statistical analyses were performed using R 4.0.4 (The R Foundation for Statistical Computing).

Patient characteristics
During the study period, 1,146,506 patients admitted to our hospitals, and 112,322 patients admitted to the ICU. Mechanically ventilated patients were 29,554, and patients with pneumonia aged over 18 years were 3,357 (Fig 1). We excluded 2,227 patients who received surgery (n = 404), had a mechanical ventilation duration < 3 d (n = 502), received ECMO (n = 58), had PaO 2 /FiO 2 � 150 mmHg (n = 1,194), and received NMB as a bolus injection (n = 69). In a total of 1,130 patients, the mean patient age was 73.1 years (SD±12.6), and 67.2% were male. NMB users were 422 (37.3%), and the mean duration of NMB use was 4.6 d (SD±5.8). A comparison of the patients' baseline characteristics is presented in Table 1. Age, CCI, and PaO 2 / FiO 2 ratio were higher in NMB nonusers than NMB users. On the other hand, modified early warning score, PEEP and the use corticosteroids, opioids, and sedatives were higher in NMB users. There were no significant differences in the APACHE II score and continuous renal replacement therapy.

Subgroup analysis
In NMB users, there was no significant difference in 30 d mortality (p = 0.055), however, 90 d mortality was significantly higher in the NMB users (p = 0.045) (Fig 3).  (Table 3).

Discussion
This multicenter study revealed that NMB use was not associated with lower 30 d mortality in mechanically ventilated pneumonia patients with moderate to severe hypoxemia. However, 90 d mortality was significantly increased in NMB users. NMB users had a longer duration of mechanical ventilation and/or ICU stay, and underwent tracheostomy more frequently than NMB nonusers. Furthermore, NMB use � 3 d was associated with higher 90-d mortality rate compared to NMB use < 3 d. Based on the results of the ROSE trial and clinical studies on sedation [18,[21][22][23], a recent practice guideline does not recommend the routine use of NMBs, even in moderate or severe ARDS [24]. This change of strategy in patients with ARDS can cause confusion for physicians regarding the use of NMBs in patients with pneumonia, which is the major cause of acute respiratory failure in the ICU [25]. In this regard, the results of our cohort provide valuable information that the use of NMBs during mechanical ventilation did not have a survival benefit in patients with severe hypoxemic pneumonia. NMBs tended to be administered to more critically ill patients because NMBs are often used in a setting where a lighter sedation strategy does not make the mechanical ventilation tolerable. We matched the clinical variables that can influence the outcomes between NMB users and nonusers as much as possible. Even after PS matching, 30 d mortality rate was not significantly different between NMB users and nonusers.  Rather, 90 d mortality rate was significantly higher in NMB users. Therefore, NMBs during mechanical ventilation should be used cautiously in hypoxemic pneumonia patients. In a recently reported meta-analysis with five randomized controlled trials, NMBs did not reduce the risk of death at 28 days (RR, 0.90; 95% CI, 0.78-1.03, P = 0.12) in ARDS patients [26]. Deep sedation accompanied by NMBs can result in negative outcomes such as mortality or delayed time to extubation [27]. It has been reported that early deep sedation is associated with higher mortality in mechanically ventilated critically ill patients [21][22][23]27]. Shehabi et al. suggested that the sedation intensity in the first 48 h was an independent predictor of increased 180 d mortality (HR [95% CI], 1.29 [1.15-1.46], p<0.001) [21]. In the multivariable Cox proportional hazard regression models, depth of sedation was positively correlated with mortality. They suggested that light sedation could be a goal to improve patients' outcomes in the early stage of mechanical ventilation [21,22,27]. Although we did not present the data of sedation intensity, there is a possibility that NMB users were more deeply sedated than NMB nonusers. Therefore, NMBs should be avoided whenever possible in critically ill patients who can tolerate ventilation with a lighter sedation according to recent ARDS guidelines [24].
NMBs have some favorable effects in patients with ARDS. NMB infusion is associated with an improvement in oxygenation and can be beneficial in increasing expiratory transpulmonary pressure in moderate to severe ARDS patients [28]. Ho et al. reported that the PaO 2 /FIO 2 ratio at 48 h in moderate to severe ARDS patients was higher in NMB users than nonusers, and the risk of barotrauma was lower in NMB users than nonusers (RR 0.55 [95% CI: 0.35-0.85], P = 0.007) [26]. On the other hand, NMB use is associated with poor outcomes such as delayed extubation, increased delirium, and a longer duration of mechanical ventilation [21][22][23]27,29]. In accordance with previous studies, our results revealed that NMB users had longer durations of ICU stay and mechanical ventilation. These may be associated with the higher incidence of tracheostomy in NMB users.
Concerns regarding NMB use include not only early deep sedation but also the prolonged use of NMBs. According to recent guidelines and clinical studies, the use of NMBs for up to 48 h is recommended [3,18,24,30,31]. Dodson et al. reported that long-term NMB infusion is associated with denervation-like changes, which could cause prolonged muscle paralysis [32]. Saccheri et al. reported that ICU-acquired weakness was associated with increased long-term mortality in critically ill patients [33]. It has been suggested that NMB use � 3 d can cause ICU-acquired weakness, and this may lead to increased 90 d mortality rates. Although the association between NMB use and ICU-acquired weakness remains controversial [34], we found that NMB users had a 1.4 times higher mortality rate at 90 days than NMB nonusers. If NMB is required to achieve lung protective ventilation, it is desirable to discontinue it within 3 days if possible.
This study has some limitations. First, due to the retrospective nature of the study, it was difficult to obtain some information. We did not describe the exact doses of drugs or adjuvant therapy such as prone positioning, which might have affected mortality. In addition, ventilatory parameters and respiratory mechanics such as driving pressure, plateau pressure, tidal volume, and static compliance were not collected. NMB can be used with various indications in critically ill patients such as facilitation of tracheal intubation, facilitation of mechanical ventilation, control of status asthmaticus or therapeutic hypothermia [14]. Although, we cannot demonstrate exact indication of NMB, patients who used NMB for intubation purpose would not be included in NMB users. Second, although PS methods were employed to match the potential differences between the two groups, there might have been residual confounding factors. Therefore, additional clinical studies are needed to assess the effect of NMBs in critically ill patients receiving mechanical ventilation for reasons other than ARDS.

Conclusions
NMB use was not associated with lower 30 d mortality in mechanically ventilated pneumonia patients with moderate to severe hypoxemia. Rather, NMB users had higher 90 d mortality and longer duration of mechanical ventilation or ICU stay than NMB nonusers. Furthermore, NMB use � 3 d was associated with higher 90 d mortality compared to NMB use < 3 d. Therefore, NMBs should be used with caution in critically ill pneumonia patients, and prolonged NMB use should be avoided if possible.